PROJECT SUMMARY: The initiation and maintenance of motivated behaviors often are characterized by a high degree of vigor, speed, persistence and work output, and organisms frequently make effort-related decisions based upon cost/benefit analyses. Clinical neuroscience research has characterized effort-related symptoms (anergia, psychomotor slowing, fatigue, lassitude) in psychopathology. These motivational symptoms interfere with activities of daily living, and can be highly resistant to treatment. Tests of effort-related choice allow animals to choose between high-effort alternatives that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued reward (i.e., less preferred or lower in magnitude). The ability to exert effort and select high-effort options is dependent upon neural circuits that involve mesolimbic dopamine (DA), ventral striatum, ventral pallidum, amygdala, and prefrontal cortex. Our laboratory has developed formal animal models that involve assessment of brain mechanisms regulating effort-related choice behavior. For example, rats treated with vesicular monoamine transport inhibitor tetrabenazine (TBZ), which induces or exacerbates symptoms such as fatigue in humans, can alter effort-related choice, reducing selection of the high effort alternative. These effects can be reversed by co- administration of bupropion (Wellbutrin), which inhibits catecholamine uptake, and several dopamine transport (DAT) inhibitors. This pattern of effects is consistent with data from human clinical neuroscience on effort-related motivational dysfunctions in psychopathology, and the effects of drugs that act on dopamine (DA). However, what is missing from this picture is the development of a physiological marker in the animal studies that can be easily translatable to human clinical research. Recent studies have demonstrated that there are electroencephalographic (EEG) markers of frontal cortex activity that are characteristic of engagement in motivated behavior and anticipation of reward, and that these markers are reduced in depressed people. Moreover, these effects are significantly correlated with dysphoria and lassitude in depressed individuals. Therefore, the proposed studies will focus on the development of frontal cortex EEG and local field potential (LFP) activity in behaving rats that are performing effort-based decision-making tasks. These rats will be tested under baseline conditions, and also after pharmacological challenges that produce effort-related motivational effects, including challenges to relevant forebrain circuits using chemogenetic methods. This research could lead to a greater understanding of the circuit mechanisms that underlie the regulation of effort-based aspects of motivation, and may provide valuable preclinical animal data that would contribute to the development of biomarkers for the therapeutic effects of agents that act upon motivational symptoms in psychopathology. This combination of physiological, behavioral, pharmacological and chemogenetic methods meets the ultimate goal of this RFA, in the sense that it may provide preclinical procedures and circuit level findings that ultimately can be translatable to methods that are applicable to human clinical neuroscience.